The purposes of this project were: 1) to determine alterations in the metabolism of enkephalins and dynorphins in the limbic-basal ganglia regions after chemical- or electrically-induced seizures; 2) to study the possible roles of brain opioid peptides in seizure-induced changes in hippocampal excitability. Previous studies showed that stimulation of perforant path, which projects from the entorhinal cortex to the dentate gyrus of the hippocampus, elicits a behavioral response, wet dog shakes, and decreases the level of dynorphin in the hippocampus. This study examined the molecular mechanisms underlying the perforant path stimulation-induced reduction in dynorphin. It is well-documented that glutamate is a neurotransmitter released from the perforant path. We have reported that stimulation of perforant path increased the extracellular concentration of glutamate in the hippocampus measured by microdialysis technique in free moving rats. Thus, it is likely that glutamate may regulate the metabolism of dynorphin in the dentate granule cells. To test this possibility, we employed a glutamate antagonist, gamma-D-glutamylglycine (gamma-DDG), which binds non-selectively to different glutamate receptor subtypes. Daily DGG pretreatment almost abolished WDS at control threshold intensities, and significantly inhibited stimulation-induced decrease of DYN-IR in both dorsal and ventral hip- pocampus. In situ hybridization using a (3 5)S-labeled oligodeoxyribonucleotide probe demonstrated a clear depletion of DYN mRNA signal in dentate granule cell layer of ACSF-treated animals. This depletion was completely prevented in DGG-treated rats. These data strongly suggest that glutamate as the endogenous transmitter at perforant synapses mediates stimulation-induced synaptic excitation and regulates the release and biosynthesis of dynorphin peptides in dentate granule cells. This project will be terminated September 30, 1990.